Victoria Atkinson, MD
Long-term data continue to show sustained improvements in overall survival (OS) with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) as a frontline treatment for patients with advanced melanoma, according to two presentations at the 2015 Society for Melanoma Research Congress.
In the phase III CheckMate-066 trial, the 2-year OS rate with frontline nivolumab was 57.7% compared with 26.7% for dacarbazine.1
Additionally, in a phase Ib study, the combination of nivolumab and ipilimumab showed an OS rate of 68% at a median follow-up of 32.7 months.2
“This trial is the longest follow-up that we have for patients from a phase III trial for a PD-1 antibody. It shows the highest 2-year survival for any PD-1 therapy in advanced melanoma,” study author Victoria Atkinson, MD, of Princess Alexandra Hospital and Gallipoli Medical Research Foundation, Queensland, Australia, told OncLive
at the conference. “Nivolumab is a highly effective treatment, which is significantly improving overall survival for patients with good quality of life.”
The FDA is currently reviewing an application for nivolumab as frontline therapy for patients with advanced melanoma, based on the CheckMate-066 trial. The agency is scheduled to make a decision regarding the application by November 27, 2015.
In the phase III trial, 418 untreated patients were randomized in a 1:1 ratio to receive nivolumab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1000 mg/m2
every 3 weeks (n = 208). Of the patients enrolled, 61% had stage M1c disease and 36.6% had an elevated lactate dehydrogenase level. The primary endpoint of the study was OS. Secondary endpoints included progression-free survival (PFS), objective response rates (ORR), and quality of life.
After a minimum follow-up of 15.1 months, median OS was not yet reached for patients receiving nivolumab compared with 11.2 months in the dacarbazine arm (HR, 0.43; 95% CI, 0.33-0.57; P
<.001). The 1-year OS rates were 70.7% and 46.3%, for nivolumab and dacarbazine, respectively. Additionally, following progression in the dacarbazine arm, 13% of patients (n = 27) went on to receive nivolumab.
Median PFS was 5.4 months with nivolumab versus 2.2 months for dacarbazine (HR, 0.42; 95% CI, 0.32-0.53; P
<.001). With nivolumab, the 1- and 2-year PFS rates were consistent, at 44.3% and 39.2%, respectively.
The ORR was 42.9% with nivolumab versus 14.4% with dacarbazine. A complete response was achieved by 11% of patients with nivolumab compared with 1% for dacarbazine. At the analysis, 81% of responses in the nivolumab arm remained ongoing.
“This data reassures us that the responses are maintained. Those who do obtain a response with nivolumab have a maintained response,” Atkinson said. “With the two year overall survival being so high, we’re seeing a plateauing of the curve. We hope that with further follow-up we will see maintained responses.”
All-grade adverse events (AEs) were similar between each arm but grade ≥3 AEs were less common with nivolumab (13% vs 17%). The most frequently reported all-grade AEs in patients treated with nivolumab were pruritus (22%), diarrhea (18%), and rash (18%). Altogether, AEs led to discontinuation in just 6% of patients in the nivolumab arm.
“The highest toxicities with nivolumab were fatigue and arthralgias,” said Atkinson. “These are very easily managed side effects, and we see that the toxicity profile is better than chemotherapy,”
Patient characteristics, such as disease burden, should be utilized to tailor treatment for patients with advanced melanoma, according to Atkinson. Those with a lower burden of disease who are frail are ideal candidates for nivolumab monotherapy. However, patients with high-risk characteristics, for which a rapid response is needed, should receive a combination of nivolumab and ipilimumab. In either scenario, PD-L1 expression did not seem to play a significant role, Atkinson advised.
“For melanoma, PD-L1 shouldn’t determine whether we give nivolumab monotherapy,” she said. “Regardless of PD-L1 status, you live longer with nivolumab.”
In the smaller phase Ib study, labeled Study 004, the combination of nivolumab and ipilimumab was explored at various dosing schedules for patients with unresectable or metastatic melanoma. In 3 cohorts that received similar treatment schedules (n = 53), the ORR with the combination was 42% and the median duration of response was 22.3 months. Complete responses were seen in 21% of patients treated with the combination.
In another cohort that received the combination every 3 weeks for 12 weeks followed by nivolumab alone every 3 weeks for 12 weeks (n = 41), the 18-month OS rate was 68%. The ORR was 44%, with complete responses in 17% of patients. The median duration of response was 13.7 months.